The mammalian cochlea is controlled by two neuronal feedback pathways, the medial and lateral olivocochlear (OC) systems, which target, respectively, outer hair cells and cochlear afferent fibers. Cochlear effects of the medial OC system have been extensively studied for 50 years; however, the function of lateral (L)OC system remains poorly understood, because it has been impossible to activate, record from, or selectively eliminate the efferent neurons comprising this pathway. Several lines of indirect evidence have suggested roles in 1) modulating stimulus coding in the auditory nerve, 2) protecting the ear from acoustic injury and/or 3) shaping the normal development of the inner ear and its afferent innervation. However direct demonstration of LOC action in the cochlea has been lacking until now: recent work in our laboratory, and elsewhere, has provided new techniques that allow direct approaches to the study of LOC effects. We have shown that the LOC can be activated by shocking the inferior colliculus and have documented slow enhancing and slow suppressive effects on auditory nerve response. In Aim 1, we will pharmacologically dissect these novel LOC effects to determine which neurotransmitters and receptors mediate them. We have succeeded in selectively lesioning the LOC system by stereotaxic injections in the brainstem. Thus, in Aim 2, we will surgically dissect the role of the LOC in shaping normal stimulus coding in the auditory nerve and test the hypothesis that the LOC system plays a role in protecting the ear from acoustic injury. We have begun to exploit the power of genetic manipulation available in mouse transgenic and knockout models to probe OC function by studying effects of elimination or over expression of key transmitter or receptor molecules. We have also developed a variety of techniques for cochlear phenotypic analysis in the mouse including techniques to record from single auditory nerve fibers. Thus, in Aim 3, we will genetically dissect the role of different transmitters and receptors utilized by the LOC system by phenotypic analysis of carefully selected mutant mouse lines already produced in other laboratories. Together, these three complementary approaches will provide the first direct assessment of the functional roles of this major feedback neuronal pathway, which is a universal component of the mammalian ear.